We propose to use the GATA-1low murine model as a tool to define the biologic mechanisms underlying the abnormal hematopoietic stem cell (HSC) and progenitor cell (HPC) trafficking and extramedullary hemopoiesis that characterizes idiopathic myelofibrosis (IM) and identify new targets for the development of drugs to treat this disorder. During this project we will test the hypothesis that HSC/HPC mobilization occurs at specific stages of the disease and that abnormal cell trafficking requires either the generation of a specific cell type (the extramedullary hematopoietic initiating cell, EMH-IC) or mobilization of both HSC/EPC and mesenchymal stem cells (MSC) and/or endothelial progenitor cells (EPC), responsible for generating a permissive hematopoietic microenvironment in a variety of extramedullary sites. To test this hypothesis we will: Specific Aim 1) To characterize the degree of HSC/HPC and MSC/EPC mobilization and trafficking during the course of the development of myelofibrosis in GATA-1low mice. Specific Aim 2) To identify the mechanisms underlying the development of abnormal HSC/HPC trafficking and extramedullary hemopoiesis in GATA-1low mice. Specific Aim 3) To identify treatment strategies for the treatment of each stage of the disease in GATA-1low mice. Relevance: IM is a hematological malignancy associated with abnormal stem cell trafficking and increased extramedullary hematopoiesis. We believe that a side-by-side investigation of the mechanisms leading to abnormal HSC/HPC trafficking and extramedullary hematopoiesis in the mouse model (Project 4) and IM patients (Project 5) will represent a powerful and effective approach to identify the optimal treatment for IM.